Congestive heart failure (CHF) occurs in over 5 million individuals in the United States today, and 500,000 additional cases are diagnosed each year. This condition is the leading cause for inpatient hospitalizations within the U.S. and is associated with high cardiac morbidity and mortality. (A. H. Assoc. (2006) Heart and Stroke Statistical Update: American Heart Association, Dallas, Tex.) CHF, systolic or diastolic, can result from a variety of structural or functional cardiac disorders or events that impair the heart's pump function. In ischemic heart disease, one of the major causes of CHF, necrotic myocyte death produces a vicious cycle of ventricular enlargement, increased myocyte fiber stress (particularly in the border zone) and eccentric myocyte hypertrophy (post-MI remodeling). Follwing an acute myocardial infarction (AMI), for example, necrotic tissue is replaced by fibrotic scar tissue to maintain the integrity of the ventricle, and, around this aneurysm, the infarct or a border zone (BZ) of hypocontractile and thinned myocardium develops and becomes subjected to substantially increased myocyte fiber stresses during the cardiac cycle. These increased stresses and abnormal strain on the region has been implicated in the pathological remodeling of the ventricle after an ischemic event, resulting in infarct extension and expansion and ultimately leading to congestive heart failure.
Attempts have also been made to address AMI injuries through various approaches. Drug therapy (ACE inhibitors and BETA blockers) has been shown to slow the remodeling that occurs after AMI, but has not been associated with return to normal left ventricular (LV) size and function. Solid organ cardiac transplantation is limited by donor shortage, and assist device therapy, although promising, is limited by persistent thrombotic events, infection, long-term materials compatibility, and the lack of an implantable power supply. Because of deficiencies in medical and standard surgical therapy for heart failure, innovative surgical procedures that reduce LV size or change LV shape are being investigated. Aneurysm repair, and radiofrequency infarct heating reduce LV volume, but LV function is either unchanged or mildly reduced. Partial left ventriculectomy reduces LV volume and wall stress, but significantly reduces LV function. Finally, passive cardiac constraint (Acorn cardiac support device, Acorn Cardiovascular) and shape change therapy with a novel tensioning device (Myosplint, Myocor) are promising, but seem unlikely to lead to large improvements in LV function.
Other approaches through tissue engineering and cell transplantation, with or without carrier matrices, into the infarct region have also been attempted to improve regional and global pump function, with mixed results. Survival of engraftment of the implanted cells has been poor and conclusive myocyte regeneration elusive despite demonstrated reduction in post-infarct loss of myocardial function with cellular and cellular/matrix injection. As such, there is a need for additional methods to stabilize the myocardium. The present invention provides compositions and methods useful in stabilizing the myocardium and mitigating function loss following ischemic injury to the heart.